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J Natl Cancer Inst. 2014 Aug 15;106(8). pii: dju183. doi: 10.1093/jnci/dju183. Print 2014 Aug.

Hyperthermia inhibits recombination repair of gemcitabine-stalled replication forks.

Author information

  • 1Department of Surgery, University of Arizona, Tucson, AZ (MR); Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (MR, CZ, BTC, HL, SJC, SAC); Department of Surgery, Baylor College of Medicine, Houston, TX (SAC, SJC); Department of Chemistry, Rice University, Houston, TX (LJW, SJC).
  • 2Department of Surgery, University of Arizona, Tucson, AZ (MR); Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (MR, CZ, BTC, HL, SJC, SAC); Department of Surgery, Baylor College of Medicine, Houston, TX (SAC, SJC); Department of Chemistry, Rice University, Houston, TX (LJW, SJC). steven.curley@bcm.edu.

Abstract

BACKGROUND:

Gemcitabine is a potent nucleoside analogue against solid tumors, but development of drug resistance is a substantial problem. Removal of gemcitabine incorporated into DNA by repair mechanisms may contribute to resistance in chemo-refractory solid tumors. Human hepatocellular carcinoma (HCC) is usually very chemoresistant to gemcitabine.

METHODS:

We treated HCC in vitro and in vivo (orthotopic murine model with human Hep3B or HepG2 xenografts, 7-10 CB17SCID mice per group) with gemcitabine. The role of homologous recombination repair proteins in repairing stalled replication forks was evaluated with hyperthermia exposure and cell-cycle analysis. The Student t-test was used for two-sample comparisons. Multiple group data were analyzed using one-way analysis of variance. All statistical tests were two-sided.

RESULTS:

We demonstrated that Mre11-mediated homologous recombination repair of gemcitabine-stalled replication forks is crucial to survival of HCC cells. Furthermore, we demonstrated inhibition of Mre11 by an exonuclease inhibitor or concomitant hyperthermia. In orthotopic murine models of chemoresistant HCC, the Hep3B tumor mass with radiofrequency plus gemcitabine treatment (mean ± SD, 180±91mg) was statistically significantly smaller compared with gemcitabine alone (661±419mg, P = .0063).

CONCLUSIONS:

This study provides mechanistic understanding of homologous recombination inhibiting-strategies, such as noninvasive radiofrequency field-induced hyperthermia, to overcome resistance to gemcitabine in refractory human solid tumors.

© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

PMID:
25128695
[PubMed - indexed for MEDLINE]
PMCID:
PMC4155430
[Available on 2015/8/1]
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